TRAILBLAZER-ALZ
(2021)Objective
Donanemab - To evaluate the safety and efficacy of donanemab, an anti-amyloid plaque antibody targeting N-terminal pyroglutamate Aβ, in patients with early symptomatic Alzheimer's disease with confirmed tau and amyloid pathology on PET
Study Summary
• The key secondary endpoint (CDR-SB) was not significant (difference −0.36; P not significant), causing the testing hierarchy to fail; most other secondary clinical outcomes were non-significant
• Donanemab achieved robust amyloid clearance: 67.8% of patients reached amyloid-negative status by 76 weeks, with an 85-centiloid reduction vs placebo
• ARIA-E occurred in 26.7% of donanemab patients (6.1% symptomatic); no brain macrohemorrhages were observed
Intervention
Donanemab (humanized IgG1 anti-pyroglutamate Aβ antibody) 700 mg IV for first 3 doses then 1400 mg every 4 weeks for up to 72 weeks, with dose reduction/switch to placebo based on amyloid PET clearance criteria; vs matched placebo
Inclusion Criteria
Age 60–85, early symptomatic AD (prodromal AD or mild AD dementia), MMSE 20–28, flortaucipir PET showing intermediate tau (SUVR 1.10–1.46), florbetapir PET amyloid positive (≥1.17 SUVR / ≥37 centiloids)
Study Design
Arms: Donanemab (700 mg x3 then 1400 mg IV q4wk), Placebo
Patients per Arm: Donanemab 131, Placebo 126
Outcome
• Key secondary endpoint CDR-SB not significant (difference −0.36; 95% CI −0.83 to 0.12), causing testing hierarchy failure
• Amyloid PET showed 85-centiloid reduction with donanemab vs placebo at 76 weeks; 67.8% achieved amyloid-negative status; no significant effect on global tau load or hippocampal volume
Bottom Line
Donanemab met the primary endpoint, showing 32% less decline on iADRS vs placebo at 76 weeks (P=0.04), but fell short of the prespecified goal of 50% slowing. The key secondary endpoint (CDR-SB) was not significant, causing the testing hierarchy to fail. Donanemab achieved robust amyloid clearance (67.8% amyloid-negative by 76 weeks) but did not significantly affect global tau load or hippocampal volume. ARIA-E occurred in 26.7% of donanemab patients. As a phase 2 trial with 257 patients, the results were promising but insufficient to establish clinical efficacy, leading to the larger TRAILBLAZER-ALZ 2 phase 3 trial.
Major Points
- TRAILBLAZER-ALZ was a phase 2, randomized, double-blind, placebo-controlled trial of donanemab in 257 patients with early symptomatic AD across 56 sites in the US and Canada
- Unique enrollment criteria required both tau PET (flortaucipir, intermediate range SUVR 1.10–1.46) and amyloid PET (florbetapir, ≥37 centiloids) positivity, selecting a narrower AD population with confirmed dual pathology but excluding high-tau (advanced) disease
- Primary endpoint met: iADRS decline was −6.86 with donanemab vs −10.06 with placebo (difference 3.20; 95% CI 0.12–6.27; P=0.04), representing 32% slowing but not meeting the prespecified 50% goal
- Key secondary endpoint CDR-SB was not significant (difference −0.36; 95% CI −0.83 to 0.12), causing the hierarchical testing procedure to fail; no definitive conclusions from remaining secondary outcomes
- ADAS-Cog13 showed a nominally significant difference (−1.86; 95% CI −3.63 to −0.09), but ADCS-iADL (1.21; 95% CI −0.77 to 3.20) and MMSE (0.64; 95% CI −0.40 to 1.67) did not
- Donanemab achieved rapid and substantial amyloid clearance: 85-centiloid reduction vs placebo at 76 weeks; 40% amyloid-negative by 24 weeks, 59.8% by 52 weeks, 67.8% by 76 weeks
- Innovative dose-adjustment protocol: donanemab was reduced or switched to placebo based on amyloid PET clearance milestones (54.7% switched to placebo by week 56)
- No significant effect on global tau load on flortaucipir PET, though prespecified regional analyses suggested reduced tau accumulation in frontal and temporal lobes
- Greater decrease in whole-brain volume and greater increase in ventricular volume with donanemab vs placebo; no significant change in hippocampal volume
- ARIA-E occurred in 26.7% of donanemab patients vs 0.8% placebo; symptomatic ARIA-E in 6.1%; higher incidence in ApoE ε4 carriers (ε4/ε4: 44.0%, ε3/ε4: 30.9%, ε3/ε3: 11.4%)
- Antidrug antibodies detected in approximately 90% of donanemab-treated participants
- A combination-therapy arm (donanemab + BACE1 inhibitor LY3202626) was discontinued early due to futility in a separate phase 2 trial of the BACE1 inhibitor
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, multicenter phase 2 trial
- Randomization
- Yes
- Blinding
- Double-blind. Safety assessments performed by site investigators unaware of group assignments. Efficacy raters were trained and unaware of trial group assignments. Unblinded florbetapir PET results used to guide dose adjustments per protocol.
- Sample Size
- 257
- Follow-up
- 76 weeks (72 weeks of dosing + 4 weeks to final assessment)
- Centers
- 56
- Countries
- United States, Canada
Primary Outcome
Definition: Change from baseline to 76 weeks in iADRS score (Integrated Alzheimer's Disease Rating Scale; range 0–144, lower = greater cognitive and functional impairment; composite of ADAS-Cog13 and ADCS-iADL)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −10.06 | −6.86 | - (0.12 to 6.27 (for difference of 3.20)) | 0.04 |
Limitations & Criticisms
- Small sample size (n=257) limits statistical power and generalizability; the trial was powered for a 50% slowing that was not achieved (only 32% observed)
- Key secondary endpoint CDR-SB was not significant, causing hierarchical testing failure; thus no confirmed clinical benefit beyond the composite iADRS primary endpoint
- The iADRS is a relatively newer composite endpoint not universally accepted as a standard in AD trials; the 3.20-point difference on a 144-point scale has uncertain clinical meaningfulness
- Very limited racial/ethnic diversity (93–96% White, <4% Black), severely limiting generalizability
- High rate of treatment discontinuation due to AEs in donanemab group (30.5% vs 7.2%), introducing potential survivor bias
- ARIA-E occurrence may have led to functional unblinding despite blinded rater design
- No significant effect on global tau load despite robust amyloid clearance, questioning whether amyloid removal translates to modification of downstream disease pathology within the study timeframe
- Paradoxical findings on volumetric MRI: greater whole-brain volume loss and ventricular enlargement with donanemab despite clinical benefit signal; mechanism unclear
- Dose heterogeneity due to ARIA-E–related dose holds and amyloid PET–based dose reduction/placebo switch complicates interpretation
- Antidrug antibody development in ~90% of participants raises questions about long-term efficacy and retreatment feasibility
- All authors with potential conflicts of interest: most are Eli Lilly employees and shareholders; trial designed, funded, and analyzed by Eli Lilly
- COVID-19 pandemic led to some telephone visits replacing on-site visits, with no efficacy data collected at those visits
Citation
N Engl J Med 2021;384:1691-1704